By Billy Candra 
A groundbreaking study from the Salk Institute, published in Proceedings of the National Academy of Sciences on May 12, 2025, has identified a critical role for estrogen-related receptors (ERRs) in repairing energy metabolism and alleviating muscle fatigue. This discovery offers a promising new therapeutic avenue for millions worldwide suffering from debilitating metabolic disorders and age-related muscle weakness, suggesting that targeting these receptors could restore vital cellular energy supplies across the body.
Understanding the Body’s Energy Powerhouses: Mitochondria and Metabolic Dysfunction
At the very core of our existence, within nearly every cell, are tiny, bean-shaped organelles called mitochondria. Often dubbed the "powerhouses" of the cell, these crucial structures are responsible for converting the food we consume into adenosine triphosphate (ATP), the primary energy currency that fuels virtually all cellular processes. This intricate cellular-level metabolism is particularly vital in muscle cells, which demand an immense and constant supply of energy to power movement, from the slightest twitch to strenuous exercise.
However, this delicate energy-generating system is susceptible to dysfunction. Mitochondrial disorders are a significant health challenge, with an estimated 1 in 5,000 individuals born with dysfunctional mitochondria. Beyond these congenital conditions, a far larger population develops metabolic dysfunction later in life, often in association with the natural aging process or as a consequence of prevalent chronic diseases. Conditions such as cancer, multiple sclerosis (MS), heart disease, dementia, and various forms of muscular dystrophy are frequently characterized or exacerbated by impaired mitochondrial function, leading to chronic fatigue, muscle weakness, and a host of other systemic issues. The global impact of these conditions is staggering, affecting hundreds of millions and severely diminishing quality of life, with limited effective treatment options currently available.
The Salk Institute’s Pioneering Research: A Legacy of Discovery
The Salk Institute, a world-renowned independent, non-profit scientific research institute established by Jonas Salk, has long been at the forefront of biological discovery, particularly in the realm of metabolism and genetics. It was within this esteemed environment that senior author Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk, made a landmark discovery in the 1980s. Dr. Evans led the identification of a pivotal family of proteins he termed "nuclear hormone receptors." These extraordinary receptors possess the ability to bind to specific hormones and, once activated, attach themselves directly to our DNA, thereby controlling which genes are turned "on" or "off." This fundamental mechanism underpins a vast array of biological processes, from development and reproduction to metabolism and immune response.
Among the diverse branches of this nuclear hormone receptor family are the estrogen-related receptors (ERRs). While structurally similar to classic estrogen receptors, their specific functions were initially much less understood. Dr. Evans’ lab, having first discovered ERRs in 1988, was among the first to recognize their potential role in energy metabolism. These receptors are notably abundant in tissues with high energy demands, such as the heart and brain, prompting Evans’ team to delve deeper into their potential regulatory role in another energy-intensive organ: skeletal muscle.
Unlocking Muscle Potential: ERRs as Indispensable Drivers
Muscles are remarkable in their adaptability. When subjected to increased demands, particularly through exercise, they respond by boosting their capacity to generate energy. One of the primary mechanisms for this adaptation is mitochondrial biogenesis – the process by which a cell increases both the number and energetic output of its mitochondria to produce more fuel. This natural response highlights the body’s inherent ability to enhance its energy infrastructure. However, for individuals afflicted with muscular and metabolic disorders, or those experiencing severe fatigue due to aging or disease, engaging in the necessary exercise to trigger this vital process is often a formidable, if not impossible, challenge. This therapeutic gap has spurred scientists to search for alternative pharmacological methods to stimulate mitochondrial biogenesis.
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," explains first author Weiwei Fan, a staff scientist in Evans’ lab. "This got us thinking — if we could understand how exercise induces mitochondrial biogenesis, we might be able to target those same mechanisms pharmacologically to trigger this process in people who are too weak to exercise."
To meticulously investigate the role of estrogen-related receptors in muscle cell metabolism, Fan and his colleagues embarked on a series of sophisticated experiments. They employed genetically modified mouse models, selectively deleting three different forms of ERRs – alpha (ERRα), beta (ERRβ), and gamma (ERRγ) – specifically within the muscle tissues, and then meticulously examined the resulting physiological and cellular effects.
Their findings revealed a nuanced interplay among the ERR subtypes. While ERRα was found to be the most abundant receptor type in muscle tissue, its isolated deletion resulted in surprisingly mild impacts on muscle function under normal conditions. Intriguingly, the researchers discovered that ERRγ, despite making up only a small fraction (approximately 4%) of the total estrogen-related receptors, possessed a remarkable compensatory capacity, stepping in to mitigate the effects of ERRα loss. However, when both ERRα and ERRγ were simultaneously deleted, the consequences were severe, leading to profound impairments in muscle mitochondrial activity, significant alterations in their shape, and a reduction in their overall size. This underscored the critical, albeit sometimes redundant, roles these receptors play in maintaining muscle energy homeostasis.
The Exercise Connection: ERRα as the Master Switch
The question then arose: if ERRα is so abundant, what is its primary, non-redundant function? The team hypothesized that its excess presence was crucial for muscles to adapt and grow in response to the demands of exercise. To test this, they subjected their mice to controlled exercise regimens on mechanical wheels. This exercise successfully triggered mitochondrial biogenesis in control mice, providing a perfect experimental model to assess ERRα’s involvement. The results were conclusive and striking: the loss of ERRα alone completely blocked exercise-induced mitochondrial biogenesis. This pivotal finding definitively established ERRα as an indispensable orchestrator of the muscle’s adaptive response to physical activity, directly linking it to the expansion of its energy infrastructure.
Previous research had already identified another key player in exercise-induced mitochondrial growth: a protein known as PGC1α, often referred to as the master regulator of mitochondria throughout the body. PGC1α is well-known for its ability to coordinate a vast network of genes involved in energy metabolism. However, a significant challenge with PGC1α as a therapeutic target is its indirect mode of action. Unlike nuclear hormone receptors such as ERRs, PGC1α cannot bind directly to genes. Instead, it relies on partnering with other proteins to exert its regulatory influence, making it a more complex and potentially less precise target for direct pharmacological intervention.
The Salk team’s subsequent investigations into muscle cells post-exercise revealed a crucial partnership: PGC1α was indeed collaborating with ERRα to drive mitochondrial biogenesis. But what set ERRα apart was its unique capability. Unlike PGC1α, ERRα can bind directly to mitochondrial energetic genes and activate them, effectively turning them "on." This direct gene-binding capacity positions ERRα as a far more attractive and potentially effective target for therapeutic drug development. A drug designed to specifically activate ERRα could bypass the complexities of PGC1α’s indirect mechanisms, offering a more direct and potent pathway to improve mitochondrial performance in muscle cells.
Broader Implications and Future Directions: A Whole-Body Impact
The ramifications of this discovery extend far beyond merely addressing muscle fatigue. "Our findings suggest that activating estrogen-related receptors could not only help fuel people’s muscles, but it could also have other beneficial effects across the whole body," notes Fan. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart." This holistic perspective underscores the systemic importance of mitochondrial health. The brain, a notoriously energy-hungry organ, and the heart, which tirelessly pumps blood throughout life, are profoundly reliant on efficient mitochondrial function. Therefore, therapies that bolster mitochondrial capacity could have far-reaching positive effects on cognitive function, cardiovascular health, and overall vitality, potentially offering new hope for conditions like Alzheimer’s disease, heart failure, and general age-related decline.
The medical community is likely to welcome these findings with significant enthusiasm. The direct targeting of ERRs offers a novel mechanism that could circumvent the limitations of current treatments for metabolic disorders, many of which focus on symptom management rather than addressing the root cause of energy deficits. Patient advocacy groups for conditions like muscular dystrophy, chronic fatigue syndrome, and various neurological disorders will undoubtedly see this as a beacon of hope for future therapies. While still in the realm of fundamental research, the clarity of the mechanism identified points towards a tangible path for pharmaceutical development.
However, challenges remain. Future research will need to delve deeper into the specific functions and regulatory mechanisms of both alpha- and gamma-type receptors. Understanding the precise nuances of their activation and interaction will be crucial for developing highly specific and effective drugs that can maximize therapeutic benefits while minimizing potential side effects. The precise molecular architecture of ERR activators, their dosage, and delivery methods will all require extensive investigation in preclinical and clinical trials. The Salk team, including other authors Hui Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan Truitt, Ruth Yu, Annette Atkins, and Michael Downes of Salk; Tae Gyu Oh of Salk and the University of Oklahoma; and Christopher Liddle of the University of Sydney, Australia, will continue this vital work.
The research was made possible through generous support from a consortium of esteemed organizations, including the National Institutes of Health (P01HL147835, DK057978, DK120515, 1R21OD030076, CCSG P30CA23100, CCSG P30 CA014195, CCSG P30 CA014195, P30 AG068635), the Department of the Navy (N00014-16-1-3159), the Larry L. Hillblom Foundation, Inc. (2021-D-001-NET), the Wu Tsai Human Performance Alliance, the Henry L. Guenther Foundation, and the Waitt Foundation. This collaborative funding underscores the widespread recognition of the profound importance of this research in advancing our understanding and treatment of metabolic diseases.
In conclusion, the Salk Institute’s latest findings on estrogen-related receptors represent a significant leap forward in our understanding of metabolic health and disease. By pinpointing ERRs, particularly ERRα, as "indispensable drivers" of mitochondrial growth and activity in muscles, this research provides a clear and direct path for developing innovative therapies. The prospect of pharmacologically boosting these receptors offers renewed hope for millions grappling with muscle fatigue and metabolic dysfunction, promising a future where cellular energy can be restored, enhancing health and quality of life across the lifespan.